Basic Science and Pathogenesis

N-methyl-D-aspartate receptors (NMDARs) are critical for synaptic transmission, with GluN2B subunits playing key roles in synaptic plasticity. Extrasynaptic GluN2Bs (ES-GluN2Bs) activate long-term depression (LTD) pathways, potentially promoting dementia in Alzheimer's disease (AD). Polysialylation of neural cell adhesion molecule (NCAM) to PSA-NCAM by ST8-α-N-acetyl-neuraminide-α-2,8-sialyltransferase-4 (ST8Sia4) and UDP-N-acetylglucosamine-2-epimerase (UDP-E) regulates synaptic remodeling and inhibits ES-GluN2B activity physiologically. However, the spatiotemporal dynamics of ES-GluN2Bs and PSA-NCAM in brain aging versus AD and how Aβ, a pathological hallmark of AD, affects these proteins remain unclear.

We examined expression levels of NMDAR subunits (GluN2A, GluN2B), ES-GluN2Bs, NCAM, and PSA-NCAM in young and old Tg2576 AD mice and wild-type (WT) controls across the cortex, prefrontal cortex, hippocampus, and midbrain using immunoblotting and pull-down assays. After this, we investigated the neurochemical effects of varying concentrations of Aβ treatment on ST8Sia4, PSA-NCAM, and UDP-E expression via protein and mRNA quantification in IMR-32 neuroblastoma cells.

Aging reduced overall GluN2B expression in both WT and AD mice (47-51%, n≥4) while increasing GluN2A expression (up to 85%, n≥4). ES-GluN2B levels were significantly elevated in AD mice (2-3-fold, n≥4), but unchanged in WT mice. PSA-NCAM expression was downregulated in AD mice (by 43-58%, n≥4), particularly in the hippocampus and prefrontal cortex, while increasing with normal aging (up to 2-fold, n≥4). Analysis of protein and mRNA expression levels following Aβ treatment in IMR-32 cells revealed significant downregulation (up to 60%) in ST8Sia4, PSA-NCAM, and UDP-E across all concentrations.

Our findings demonstrate AD-specific increases in ES-GluN2B expression and a significant downregulation in PSA-NCAM levels, distinguishing AD from normal aging, potentially driven by Aβ-induced downregulation of biosynthetic enzymes ST8Sia4 and UDP-E. This underscores a potential link between PSA-NCAM expression and Aβ activity in AD, as well as possible therapeutic targets for AD intervention.